癌变
生物
肾透明细胞癌
H3K4me3
基因沉默
癌症研究
细胞生长
效应器
下调和上调
细胞
表观遗传学
细胞生物学
基因表达
生物化学
基因
肾细胞癌
发起人
内科学
医学
作者
Jin Zhou,Jeremy M. Simon,Chengheng Liao,Cheng Zhang,Lianxin Hu,Giada Zurlo,Xijuan Liu,Cheng Fan,Austin J. Hepperla,Liwei Jia,Vanina T. Tcheuyap,Hua Zhong,Roy Elias,Jin Ye,W. Mike Henne,Payal Kapur,Deepak Nijhawan,James Brugarolas,Qing Zhang
出处
期刊:Molecular Cell
[Elsevier]
日期:2022-08-01
卷期号:82 (16): 3030-3044.e8
被引量:28
标识
DOI:10.1016/j.molcel.2022.06.003
摘要
Characterized by intracellular lipid droplet accumulation, clear cell renal cell carcinoma (ccRCC) is resistant to cytotoxic chemotherapy and is a lethal disease. Through an unbiased siRNA screen of 2-oxoglutarate (2-OG)-dependent enzymes, which play a critical role in tumorigenesis, we identified Jumonji domain-containing 6 (JMJD6) as an essential gene for ccRCC tumor development. The downregulation of JMJD6 abolished ccRCC colony formation in vitro and inhibited orthotopic tumor growth in vivo. Integrated ChIP-seq and RNA-seq analyses uncovered diacylglycerol O-acyltransferase 1 (DGAT1) as a critical JMJD6 effector. Mechanistically, JMJD6 interacted with RBM39 and co-occupied DGAT1 gene promoter with H3K4me3 to induce DGAT1 expression. JMJD6 silencing reduced DGAT1, leading to decreased lipid droplet formation and tumorigenesis. The pharmacological inhibition (or depletion) of DGAT1 inhibited lipid droplet formation in vitro and ccRCC tumorigenesis in vivo. Thus, the JMJD6-DGAT1 axis represents a potential new therapeutic target for ccRCC.
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